The total synthesis of a variety of compounds with demonstrated neurological activity is proposed. Our general aim is to develop new efficient synthesis procedures so that the target compounds and important analogs will be available, via total synthesis, in quantities sufficient for detailed neurological evaluation. Targets include alkaloids of the strychnos, aspidosperma, amaryllidaceae, and melodinus families. Specific targets are d,l-akuammicine, (-)-strychnine, (+)-vindoline, d, l-pretazettine, d,l-meloscine, d,l-scandine, and analogs of pumiliotoxin C and gephyrotoxin. Synthetic targets and intermediates will be tested for neurological activity in the laboratories of Dr. John Daly and Professor E. X. Alburquerque, while broad biological screening will be done by the Shell Development Company. The strychnos alkaloids exhibit powerful neurological activities and members of this group are the most paralytic neuromuscular blocking agents known today. We aim to exploit synthetic technology developed during the current grant period to achieve a practical synthesis of the complex strychnos alkaloid (-)-strychnine. Dimeric vinca alkaloids, with vindoline as one subunit, are clinically used oncolytic agents (e.g. vinblastine and vincristine). These agents possess powerful neurological activities, which frequently interfere with clinical use of these agents. We aim to extend the aspidosperma alkaloid synthesis developed during the current grant period to achieve the first synthesis of (+)-vindoline. Our synthetic route could, for the first time, make vindoline analogs with modified A rings available. Our collaboration in the neurological studies of gephyrotoxin and pumiliotoxin C analogs will be continued. Synthetic analogs with activities greater than the natural agents have already been developed. Our proposed studies are largely founded on the tandem aza-Cope rearrangement-Mannich cyclization reaction developed in our laboratory during the current grant period.